P628: UPDATED ANALYSIS OF BELLWAVE-001: A PHASE 1/2 OPEN-LABEL DOSE-EXPANSION STUDY OF THE EFFICACY AND SAFETY OF NEMTABRUTINIB FOR THE TREATMENT OF B-CELL MALIGNANCIES
Authors: Jennifer Woyach, Ian W. Flinn, Farrukh Awan, Herbert Eradat, Danielle M. Brander, Michael Tees, Sameer Parikh, Tycel Phillips, Razi Ghori, Ima Paydar, Mohammed Z. H. Farooqui, John C. Byrd, Deborah Stephens
Journal: HemaSphere (2023)

Background: Bruton tyrosine kinase inhibitors (BTKis) have become a standard of care for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but resistance can develop. The most common mechanism of resistance to BTKis is mutation to BTK at C481 (cysteine-binding site). Nemtabrutinib inhibits both wild-type and C481S-mutant BTK. Initial results from the phase 1/2 BELLWAVE-001 study (NCT03162536) showed that the RP2D of nemtabrutinib (65 mg QD) had a manageable safety profile and promising antitumor activity in heavily pretreated patients (pts) with relapsed or refractory (R/R) CLL/SLL, including pts whose disease progressed after prior covalent BTKis (Woyach et al. Blood. 2021;138 (suppl 1):392). Aims: Evaluate efficacy and safety of the RP2D of nemtabrutinib in pts with hematologic malignancies. Methods: In this open-label, single-arm, phase 1/2 study, pts with CLL/SLL were enrolled in cohort A (R/R CLL/SLL with ≥2 prior therapies, including a covalent BTKi, with a C481 mutation) or cohort B (R/R CLL/SLL with ≥2 prior therapies, intolerant to a BTKi, without a C481 mutation) and pts with B-cell non-Hodgkin lymphoma were enrolled. Pts received nemtabrutinib 65 mg QD until unacceptable toxicity, disease progression, or other discontinuation criteria were met. Primary end points were ORR (for CLL/SLL pts, per 2018 iwCLL criteria, by investigator), safety, and RP2D. Secondary end points were DOR and safety. Efficacy analysis included CLL/SLL pts treated with ≥1 28-day cycle of nemtabrutinib 65 mg QD with ≥1 disease assessment after treatment initiation. The safety analysis included all pts with hematologic malignancies who received ≥1 dose of nemtabrutinib 65 mg QD. An exploratory analysis evaluated efficacy in pt subgroups based on treatment history (prior BTK and BCL2 inhibitors) and genetic status (C481S-mutated BTK, del(17p), and IGHV unmutated). Results: 112 pts were enrolled and treated with nemtabrutinib 65 mg QD; 57 had CLL/SLL. Among pts with CLL/SLL, median age was 66 years; 16 pts (28%) were female, and 50 (88%) had ECOG PS ≤1. Among pts with CLL/SLL, the median number of prior therapies was 4 (range, 1-18); 54 pts (95%) had prior BTKi therapy; 24 (42%) had prior BTKi and BCL2i therapy; 36 (63%) had C481S-mutated BTK; 18 (32%) had TP53 mutation; 19 (33%) had del(17p); and 30 (53%) had no IGHV mutation. At data cutoff (April 8, 2022), median follow-up for all pts treated with nemtabrutinib was 4.8 months (range, 0.1-38.8). Among the CLL/SLL pts, 32 had an objective response (ORR, 56% [95% CI, 42-69]; 2 CR; 15 PR; 15 PR-L). Of the 32 pts who responded, median DOR was 24.4 months (95% CI, 13.9-not evaluable [NE]). Median PFS was 26.3 months (95% CI, 10.1-NE). Efficacy by subgroups is presented in the table. Among all pts with B-cell malignancies treated with nemtabrutinib 65 mg QD (n = 112), 82 (73%) had any-grade treatment-related AEs, most common (≥15%) were dysgeusia (21%) and neutrophil count decreased (20%). Grade 3 or 4 treatment-related AEs occurred in 45 pts (40%); most commonly (≥5%) neutrophil count decreased (17%). The most common AEs of special interest (≥20%) were hypertension (30%) and arthralgia (20%). Treatment-related discontinuations occurred in 15 pts (13%). Of 57 pts with CLL/SLL, 39 (68%) discontinued treatment, most commonly because of clinical disease progression (PD) and other (10 [18%], each), and AEs (8 [14%]). No deaths were attributed to treatment. Summary/Conclusion: Nemtabrutinib 65 mg continued to show promising and durable antitumor activity in pts with R/R CLL/SLL and a manageable safety profile in pts with hematologic malignancies.Keywords: Clinical trial, Chronic lymphocytic leukemia